Memory consolidation promoting agent and method of use

ABSTRACT

A medicament for promoting memory consolidation, which comprises, as an active ingredient, a non-natural retinoid, preferably a retinoid having a basic skeleton comprising an aromatic ring bound with an aromatic carboxylic acid or tropolone by means of a bridging group, more preferably 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid or 4-[(3,5-bis-trimethylsilylphenyl)-carboxamido]benzoic acid.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a national stage of International ApplicationNo. PCT/JP2005/004051, filed Mar. 9, 2005, which claims the benefit ofProvisional Application No. 60/622,618, filed Oct. 28, 2004, and alsoclaims priority to Japanese Patent Application No. 2004-066996, filedMar. 10, 2004.

TECHNICAL FIELD

The present invention relates to a medicament which promotes memoryconsolidation.

BACKGROUND ART

Memory is a system in which nerves make complicated neural circuits inthe brain with growth thereof, and specific information is consolidatedin the neural circuits in a reproducible state. It was discovered thatdestroyed connecting synapses of nerves were restored in the hippocampusof the limbic system which is responsible for memory. It came to beinferred that new neural circuits are formed in the brain depending onthe necessity for memory. It has also become revealed that hierarchicallevels of memory exist, such as preservation of short-term memory andlong-term memory and reproduction thereof. Short-term memory correspondsto a level that information is preserved only a short time, and thenwhen it becomes necessary to memorize that information, the short-termmemory changes to long-term memory, and this information is consolidatedas memory which is not easily forgotten. It is considered that long-termmemory is transmitted from the hippocampus to the cerebral cortex andstored in the cerebral cortex over many hours. Long-term memory isclassified into declarative memory and procedural memory depending on acontent to be memorized. Declarative memory is memory which can beexplained by means of language, and procedural memory is what is calledas memory of skill, which is acquired by a person and unconsciously usedby the person. Declarative memory may sometimes be further classifiedinto episodic memory and semantic memory. Episodic memory is memory ofpersonal experience and semantic memory is that of general knowledge andinformation such as those acquired by study. The episodic memory ismainly obstructed in the Alzheimer disease, and in the disease, patientsoften cannot memorize experiences, i.e., what, when and where they havedone.

Retinoid is a generic term for referring to compounds that bind toreceptors required for all trans-retinoic acid and 9-cis-retinoic acidto exhibit physiological functions thereof (three kinds of subtypes ofthe receptor exist for each compound), and thereby exhibit actionssimilar to those of retinoic acid or a part of the actions. Concerningthe action of retinoid on neurodegenerative diseases, for example, ithas been suggested that the retinoids described in Japanese PatentUnexamined Publication (KOHYO) No. 2000-502707 are effective forneurodegenerative diseases (e.g., Alzheimer disease). It has also beenreported that expression of dopamine D2 receptor is increased byactivation of a retinoid receptor (Proc. Natl. Acad. Sci., USA, 94, pp.14349-14354, 1997). As for relationship between a retinoid and memory,it has been reported that reduction of memory in aged mice is recoveredby retinoic acid (150 μg/kg, s.c.) (J. Neurosci., 21, pp. 6423-6429,2001). However, what is suggested in this article is suppression ofreduction of already consolidated long-term memory by retinoic acid, andthe article does not suggest nor teach any action of retinoic acid onthe consolidation process of short-term memory to long-term memory.

[Patent document 1] Japanese Patent Unexamined Publication (KOHYO) No.2000-502707

[Non-patent document 1] J. Neurosci., 21, pp. 6423-6429, 2001

DESCRIPTION OF THE INVENTION Object to be Achieved by the Invention

An object of the present invention is to provide a medicament forpreventing and treating dysfunction of memory consolidation associatedwith neurodegenerative diseases and the like. More specifically, theobject of the present invention is to provide a medicament forprophylactic and/or therapeutic treatment of hypomnesia associated withneurodegenerative diseases and the like by promoting memoryconsolidation.

The inventors of the present invention conducted various researches toachieve the aforementioned object, and as a result, they found that aretinoid, having a basic skeleton comprising an aromatic ring bound withan aromatic carboxylic acid or tropolone by means of a bridging group,had a superior memory consolidation promotion effect, and this retinoidsuccessfully exhibited remarkably high efficacy for prophylactic and/ortherapeutic treatment of dysfunction of memory consolidation associatedwith neurodegenerative diseases such as Alzheimer disease and the like.The present invention was achieved on the basis of the above findings.

The present invention thus provides a medicament for promoting memoryconsolidation, which comprises as an active ingredient a non-naturalretinoid, preferably a retinoid having a basic skeleton comprising anaromatic ring bound with an aromatic carboxylic acid or tropolone bymeans of a bridging group. This medicament can be used, for example, asa medicament for prophylactic and/or therapeutic treatment ofdysfunction of memory consolidation associated with neurodegenerativediseases such as Alzheimer disease.

According to preferred embodiments of the present invention, there areprovided the aforementioned medicament, wherein the retinoid is aretinoid that binds to the retinoic acid receptor (RAR) subtype α andsubtype β, and does not substantially bind to the retinoic acid receptorsubtype γ; the aforementioned medicament, wherein the retinoid is aretinoid having a basic skeleton comprising a substituted phenyl groupand benzoic acid or tropolone bound through a bridging group; theaforementioned medicament, wherein the retinoid is4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid or 4-[(3,5-bis-trimethylsilylphenyl)carboxamido]benzoic acid; theaforementioned medicament, wherein the retinoid is a retinoid comprisingdibenzo[b,f][1,4]thiazepinylbenzoic acid as a basic skeleton; theaforementioned medicament, wherein the retinoid is4-[2,3-(2,5-dimethyl-2,5-hexano)dibenzo[b,f][1,4]-thiazepin-11-yl]benzoicacid; and the aforementioned medicament, wherein the retinoid is4-[5-(4,7-dimethylbenzofuran-2-yl)pyrrol-2-yl]benzoic acid.

From another aspect, the present invention provides use of theaforementioned retinoid for manufacture of the aforementionedmedicament; and a method for promoting memory consolidation, whichcomprises the step of administrating an effective amount of theaforementioned retinoid to a mammal including human.

From a still further aspect, the present invention provides a medicamentfor prophylactic and/or therapeutic treatment of a neurodegenerativedisease, preferably Alzheimer disease or Parkinson's disease, whichcomprises4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid or 4-[(3,5-bis-trimethylsilylphenyl)carboxamido]benzoic acid as anactive ingredient.

Effect of the Invention

The medicament of the present invention has a superior action for memoryconsolidation, and the medicament is useful as, for example, amedicament for prophylactic and/or therapeutic treatment of dysfunctionof memory consolidation associated with neurodegenerative diseases suchas Alzheimer disease.

BEST MODE FOR CARRYING OUT THE INVENTION

As the active ingredient of the medicament of the present invention,non-natural retinoids, preferably retinoids having a basic skeletoncomprising an aromatic ring bound with an aromatic carboxylic acid ortropolone by means of a bridging group can be used. More specifically,as the active ingredient of the medicament of the present invention,retinoids represented by the following general formula: B—X-A (wherein Brepresents an aromatic group which may have a substituent, X representsa bridging group, and A represents a carboxylic acid-substitutedaromatic group or tropolonyl group) can be used. In the specification,retinoid refers to compounds that bind to receptors required for alltrans-retinoic acid and 9-cis-retinoic acid to exhibit physiologicalfunctions thereof, and thereby exhibit actions similar to those ofretinoic acid or a part of the actions, and the term means compoundsthat have at least one retinoid-like action, for example, one ore moreof cell differentiating action, cell proliferation promoting action,life supporting action, and the like. Whether a certain compound is aretinoid or not can be readily determined by the method described in H.de The, A. Dejean, “Retinoids: 10 years on.”, Basel, Karger, 1991, pp.2-9. Further, while retinoids generally have a property of binding to aretinoic acid receptor (RAR), the retinoid used as the active ingredientof the medicament of the present invention is preferably a retinoid thatbinds to the subtype α (RAR α) and subtype β (RAR β) of RAR, and doesnot substantially bind to the subtype γ (RAR γ). Binding to a retinoicacid receptor subtype can also be easily confirmed by the methoddescribed in the aforementioned literature.

As the aromatic group represented by B, a phenyl group which may have asubstituent is preferred. Type, number, and substituting position of thesubstituent on the phenyl group are not particularly limited. As thesubstituent on the phenyl group, for example, a lower alkyl group can beused (in the specification, the term “lower” means a carbon number of 1to about 6, preferably 1 to 4). As the lower alkyl group, an alkyl grouphaving a linear or branched chain is preferred, and more specificexamples include methyl group, ethyl group, n-propyl group, isopropylgroup, n-butyl group, sec-butyl group, tert-butyl group, and the like.Other examples of the substituent on the phenyl group include, forexample, a lower alkoxyl group such as methoxy group, a halogen atom(the halogen atom may be any of fluorine atom, chlorine atom, bromineatom, and iodine atom), a lower alkyl-substituted silyl group such astrimethylsilyl group, and the like. As the phenyl group, for example, aphenyl group substituted with 2 to 4 of lower alkyl groups, a phenylgroup substituted with 1 or 2 of tri(lower alkyl)silyl group, And thelike are preferred, and a phenyl group substituted with 2 to 4 of loweralkyl groups, a phenyl group substituted with 2 of tri(lower alkyl)silylgroups, and the like are more preferred.

When two of the lower alkyl groups substituting on the phenyl group areadjacent to each other, they may combine together to form one or two,preferably one of 5- or 6-membered ring together with thering-constituting carbon atoms of the phenyl group to which they bind.The ring formed as described above may be saturated or unsaturated, andone or more lower alkyl groups such as methyl group and ethyl group maysubstitute on the ring. On the aforementioned formed ring, preferably 2to 4 of methyl groups, more preferably 4 of methyl groups, maysubstitute. For example, it is preferred that two adjacent lower alkylgroups which substitute on the phenyl ring combine together to form5,6,7,8-tetrahydronaphthalene ring,5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring, or the like. Asthe aromatic group represented by B, an aromatic heterocyclic group mayalso be used. Examples of such retinoid include a retinoid wherein B isa benzofuranyl group which may have a substituent, preferablybenzofuran-2-yl group, particularly preferably4,7-dimethylbenzofuran-2-yl group.

As the carboxylic acid-substituted aromatic group represented by A, acarboxylic acid-substituted phenyl group, a carboxylic acid-substitutedheterocyclic group, and the like can be used, and 4-carboxyphenyl groupis preferred. Examples of the heterocyclic carboxylic acid constitutingthe carboxylic acid-substituted heterocyclic group represented by Ainclude, for example, pyrimidine-5-carboxylic acid, and the like. As thetropolonyl group represented by A, tropolon-5-yl group is preferred.

Type of the bridging group represented by X is not particularly limited,and examples include, for example, —NHCO—, —CONH—, —N(R^(A))— (R^(A)represents a lower alkyl group, for example, cyclopropylmethyl group andthe like), —C(R^(B))(R^(C))— (R^(B) and R^(C) independently representhydrogen atom, a lower alkyl group, and the like). Further, X may be adivalent aromatic group. For example, X may be pyrrol-diyl group, or thelike. Furthermore, the bridging group represented by X and the aromaticgroup represented by B may combine together to form a ring structure.For example, the basic skeleton of the retinoid represented by B—X-A maybe dibenzo[b,f][1,4]thiazepinylbenzoic acid ordibenzo[b,f][1,4]diazepinylbenzoic acid. In the specification, the term“basic skeleton” means a main chemical structure for one or morearbitrary substituents to bind thereto.

As preferred retinoids, for example, retinoids comprising aphenyl-substituted carbamoylbenzoic acid or a phenyl-substitutedcarboxamidobenzoic acid as a basic skeleton can be used. Variousretinoids comprising a phenyl-substituted carbamoylbenzoic acid or aphenyl-substituted carboxamidobenzoic acid as a basic skeleton areknown. Typical examples of retinoids having a phenyl-substitutedcarbamoylbenzoic acid as a basic skeleton include Am80(4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid (refer to Hashimoto, Y., Cell Struct. Funct., 16, pp. 113-123,1991; Hashimoto, Y, et al., Biochem. Biophys. Res. Commun., 166, pp.1300-1307, 1990), and typical examples of retinoids having aphenyl-substituted carboxamidobenzoic acid include Tac101(4-[(3,5-bis-trimethylsilylphenyl)carboxamido]benzoic acid (J. Med.Chem., 33, pp. 1430-1437, 1990).

Preferred retinoids include, for example, compounds represented by thefollowing general formula (I):

wherein R¹, R², R³, R⁴, and R⁵ independently represent hydrogen atom, alower alkyl group, or a lower alkyl-substituted silyl group, when two ofadjacent groups among R¹, R², R³, R⁴, and R⁵ are lower alkyl groups,they may combine together to form a 5- or 6-membered ring together withthe carbon atoms of the benzene ring to which they bind (this ring mayhave one or more alkyl groups), and X¹ represents —CONH— or —NHCO—.

In the aforementioned general formula (I), as the lower alkyl grouprepresented by R¹, R², R³, R⁴, and R⁵, a linear or branched alkyl grouphaving 1 to about 6 carbon atoms, preferably 1 to 4 carbon atoms, can beused. For example, methyl group, ethyl group, n-propyl group, isopropylgroup, n-butyl group, sec-butyl group, tert-butyl group, and the likecan be used. On the aforementioned lower alkyl group, one or morearbitrary substituents may exist. Examples of the substituents include,for example, hydroxyl group, a lower alkoxyl group, a halogen atom, andthe like. Examples of the lower alkyl-substituted silyl grouprepresented by R¹, R², R³, R⁴, and R⁵ include, for example,trimethylsilyl group, and the like.

Two of adjacent lower alkyl groups selected from the group consisting ofR¹, R², R³, R⁴, and R⁵ may combine together to form one or two,preferably one of 5- or 6-membered ring together with the carbon atomsof the benzene ring to which they bind. The ring formed as describedabove may be saturated or unsaturated, or an aromatic ring, and one ormore lower alkyl groups such as methyl group and ethyl group maysubstitute on the ring. As the alkyl group which may substitute on thering, a linear or branched alkyl group having 1 to about 6 carbon atoms,preferably 1 to 4 carbon atoms, can be used. For example, methyl group,ethyl group, and the like can be used, and preferably 2 to 4 of methylgroups, more preferably 4 of methyl groups, may substitute. For example,it is preferred that 5,6,7,8-tetrahydronaphthalene ring,5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring, or the like isformed by the benzene ring on which R² and R³ substitute, and R² and R³.

Examples of other preferred retinoids include, for example, retinoidscomprising dibenzo[b,f][1,4]thiazepinylbenzoic acid ordibenzo[b,f][1,4]diazepinylbenzoic acid as the basic skeletonrepresented by B—X-A. Examples of such retinoids are described in, forexample, Japanese Patent Unexamined Publication (KOKAI) No. 10-59951.Particularly preferred examples of such retinoids include, for example,HX630(4-[2,3-(2,5-dimethyl-2,5-hexano)dibenzo[b,f][1,4]-thiazepin-11-yl]benzoicacid). Further, examples of retinoids wherein X is —N(R^(A))—, and B isan aromatic heterocyclic carboxylic acid include, for example,2-[2-(N-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-N-cyclopropylmethyl)amino]pyrimidine-5-carboxylicacid. The aforementioned HX630 and2-[2-(N-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-N-cyclopropylmethyl)amino]pyrimidine-5-carboxylicacid are retinoids known to be ligands of the receptor RXR. Further,examples of retinoids wherein X is a divalent aromatic group include,for example, 4-[5-(4,7-dimethylbenzofuran-2-yl)pyrrol-2-yl]benzoic acid.Examples of the compound wherein A is a tropolonyl group include, forexample,5-[[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]carboxamido]tropolone,and the like.

As the active ingredient of the medicament of the present invention,salts of the aforementioned retinoids may be used. For example,physiologically acceptable salts including metal salts such as sodiumsalts, potassium salts, magnesium salts, and calcium salts, ammoniumsalts, organic amine salts such as triethylamine salts, and ethanolaminesalts, and the like can be used as the active ingredient of themedicament of the present invention. The aforementioned retinoids mayhave one or more asymmetric carbons according to the types ofsubstituents, and all of arbitrary optical isomers based on theseasymmetric carbons, arbitrary mixtures of optical isomers, racemates,diastereoisomers based on two or more asymmetric carbons, arbitrarymixtures of diastereoisomers, and the like can be used as the activeingredient of the medicament of the present invention. Furthermore,geometrical isomers based on cis- or trans-configuration of double bond,arbitrary mixtures of geometrical isomers, and arbitrary hydrates orsolvates of the compounds in free forms or in the form of a salt canalso be used as the active ingredient of the medicament of the presentinvention.

The medicament of the present invention has an action of promotingmemory consolidation, and the medicament can be used as, for example, amedicament for prophylactic and/or therapeutic treatment of dysfunctionof memory consolidation associated with a neurodegenerative disease,aging, and the like. Examples of the neurodegenerative disease includeAlzheimer disease, Parkinson's disease, schizophrenia, drug dependence,abnormality of autonomic nerve, and the like, but not limited to theseexamples. In the process of memory, short-term memory changes intolong-term memory, and consolidated as memory which is not easilyforgotten. The medicament of the present invention has an action ofimproving obstruction of the process of consolidating short-term memoryas long-term memory (in the specification, this obstruction is calleddysfunction of memory consolidation), and promoting formation oflong-term memory from short-term memory. The term long-term memory usedin the specification includes declarative memory and procedural memory,and declarative memory includes episodic memory and semantic memory. Themedicament of the present invention can improve memory consolidation forany of these types of long-term memory. The memory consolidationpromoting action of the medicament of the present invention can beobjectively determined by using, for example, a passive avoidancereaction as an index, and the procedures for the determination arespecifically described in the examples of the specification. Therefore,those skilled in the art can readily confirm the action of themedicament of the present invention.

The medicament of the present invention contains one or more kinds ofsubstances selected from the group consisting of the aforementionedretinoids, salts thereof, hydrates and solvates thereof as the activeingredient. Preferred efficacy may be obtained by administering two ormore kinds of different retinoids in combination. Although theaforementioned substances, per se, may be administered as the medicamentof the present invention, they can be preferably administered as apharmaceutical composition for oral or parenteral administration thatcan be prepared by methods well known to those skilled in the art.Examples of the pharmaceutical composition suitable for oraladministration include, for example, tablets, capsules, powders,subtilized granules, granules, solutions, syrups, and the like, andexamples of the pharmaceutical composition suitable for parenteraladministration include, for example, injections, suppositories,inhalants, eye drops, nasal drops, ointments, creams, patches, and thelike.

The aforementioned pharmaceutical composition can be prepared by addingpharmacologically and pharmaceutically acceptable additives. Examples ofthe pharmacologically and pharmaceutically acceptable additives include,for example, excipients, disintegrating agents or disintegrating aids,binders, lubricants, coating agents, dyes, diluents, bases, dissolvingagents or dissolving aids, isotonic agents, pH modifiers, stabilizers,propellants, tackifiers, and the like.

Dose of the medicament of the present invention is not particularlylimited, and can be appropriately increased or decreased depending onvarious factors which should usually be taken into consideration, suchas body weight and age of a patient, symptoms and type of a disease, andadministration route. In general, for oral administration, themedicament of the present invention can be used at a dose of about 0.01to 1,000 mg per day for adults, which may be appropriately increased ordecreased.

EXAMPLES

The present invention will be more specifically explained with referenceto examples. However, the scope of the present invention is not limitedby the following examples.

Example 1

6-Week old Slc:Wistar male rats were used for the experiment afterpreliminary breeding including one week of quarantine. The animals wereindividually bred under an environment at a temperature of 22±3° C. anda humidity of 50±20% with illumination of 12 hours (8:00 to 20:00) forboth the preliminary breeding and experimental periods, and the animalswere given pellets (Labo M R Stock, Nihon Nosan Kogyo K. K.) and tapwater ad libitum. The animals were divided into groups according to bodyweights as an index (10 animals/group), and trials for acquisition andreproduction of memory were performed. Each trial was performed by usinga shuttle type avoidance test box. The box had a light room on one sideand a darkroom on the other side, an opening-and-closing type partitionwas provided between the two rooms, and the box was designed so thatonly the dark room was electrifiable. Each animal was put into the lightroom, time until the animal moved to the dark room (latent time) wasmeasured up to 5 minutes, and when the rat moved to the darkroom, thepartition was shut, and shock was given by electrification.

Each animal was subcutaneously given 0.5 mg/kg of scopolamine 30 minutesbefore the trial, and this procedure was continued for seven days.Scopolamine, which is an anticholinergic agent, is known to block themuscarinic acetylcholine receptor in the striate body and inhibitacquisition of new memory (Folia Pharmacol. Jpn., 97, pp. 351-359,1991). From the third day, the test substance (Am80:4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid, 10 mg/kg/day) was orally given 3 hours before the scopolaminetreatment. With numerical values obtained, average and standarddeviation were calculated for each group, and a homoscedasticity testwas performed by F-test between the control group (no Am80 treatment)and Am80-treated group. When homoscedasticity was observed, presence orabsence of significant difference was determined by Student's t-test,and when non-homoscedasticity was observed, presence or absence ofsignificant difference was determined by Aspin-Welch's t-test. Theresults are shown in Table 1. In the Am80-treated group, the latent timewas gradually extended from the start of the treatment, and from the 5thday, significant differences were observed with respect to the controlgroup.

TABLE 1 Dose Reaction latency (second) (mg/kg/day) 1^(a)) 2 3 4 5 6 7 0(Control) 20 ± 12 ± 21 ± 44 ±  52 ±  53 ±  57 ±  4  4  5 10  6  4  7 1015 ± 14 ± 26 ± 88 ± 149** ± 163** ± 162** ±  4  4  5 19  29  30  29^(a))Lapsed days (day) **p < 0.01, significant difference between thecontrol group and the treatment group as determined by F-t-test Averagesare indicated in the upper row, and standard errors are indicated in thelower row for each group.

Example 2

A test was performed in the same manner as that of Example 1, exceptthat scopolamine was given at a dose of 0.25 mg/kg or 0.5 mg/kg, and 2mg/kg, 5 mg/kg or 12.5 mg/kg of Am80, 30 mg/kg of Tac101(4-[(3,5-bis-trimethylsilylphenyl)-carboxamido]benzoic acid), and 10mg/kg of HX630(4-[2,3-(2,5-dimethyl-2,5-hexano)dibenzo[b,f][1,4]thiazepin-11-yl]benzoicacid) were given. Combinatory use of Am80 (5 mg/kg) and HX630 (10 mg/kg)was also similarly examined. Drug treatment was performed from the 2ndday. In the same manner as the results of Example 1, the latent time wasgradually extended in the Am80, Tac101, HX630-treated groups and theAm80 and HX630 combined use group compared with the control group.

TABLE 2 Dose (mg/kg/day) Am Tac HX Reaction latency (second) SCP 80 101630 1^(a)) 2 3 4 5 0.5 — — — 13 ± 18 ± 17 ± 23 ±  33 ±  2  3  2  3  10.25 — — — 10 ± 15 ± 15 ± 30 ±  42 ±  2  2  4  6  5 0.5 2 — — 14 ±  9 ±23 ± 24 ±  38 ±  5  1  3  3  3 0.5 5 — — 19 ± 18 ± 38 ± 52 ±  71 ±  4  2 6  5  4 0.5 12.5 — — 15 ± 24 ± 43 ± 74 ± 133 ±  4  2 10  3  12 0.25 5 —— 14 ± 15 ± 53 ± 80 ± 155 ±  3  3 14 12  17 0.5 — 30 — 19 ± 21 ± 47 ± 69± 107 ±  9  4  7  3  4 0.5 — — 10 18 ± 21 ± 30 ± 33 ±  51 ±  5  2  3  2 3 0.5 5 — 10 11 ± 17 ± 57 ± 60 ± 102 ±  3  5 11  5  12 ^(a))Lapsed days(day) Averages are indicated in the upper row, and standard errors areindicated in the lower row for each group. SCP: Scopolamine

Example 3

In the same manner as that of Example 2, scopolamine was given at a doseof 0.25 mg/kg, and 10 mg/kg of4-[5-(4,7-dimethylbenzofuran-2-yl)pyrrol-2-yl]benzoic acid (IT-K-1001)was orally given. The results are shown in Table 3. This compoundmarkedly inhibited the effect of scopolamine.

TABLE 3 Dose (mg/kg/day) IT-K- Reaction latency (second) SCP 1001 1^(a)2 3 4 5 6 7 8 — — 16 ± 134 ± 152 ± 201 ± 300 ± 292 ± 300 ± 300 ±  4  50 41  24  0  8  0  0 0.25 — 27 ±  28 ±  31 ±  43 ±  47 ±  49 ±  58 ±  73±  3  8  6  11  7  8  7  5 0.25 10 22 ±  11 ± 106 ± 115 ± 206 ± 291 ±300 ± 281 ±  4  2  43  41  46  9  0  19 ^(a))Lapsed days (day) Averagesare indicated in the upper row, and standard errors are indicated in thelower row for each group. SCP: Scopolamine

Industrial Applicability

The medicament of the present invention has a superior action for memoryconsolidation, and is useful as, for example, a medicament forprophylactic and/or therapeutic treatment of dysfunction of memoryconsolidation associated with neurodegenerative diseases such asAlzheimer disease.

1. A method for promoting formation of long-term memory from short-termmemory, comprising administering to a mammal, in need of consolidationof short-term as long-term memory, a therapeutically effective amount ofa composition to promote memory consolidation of short-term memory aslong-term memory, the composition comprising4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid as an active ingredient.
 2. The method according to claim 1,wherein the promoting formation of long-term memory from short-termmemory comprises therapeutic treatment of dysfunction of memoryconsolidation associated with a neurodegenerative disease.
 3. The methodaccording to claim 2, wherein the dysfunction of memory consolidationassociated with a neurodegenerative disease comprises Alzheimer disease.4. The method according to claim 2, wherein the dysfunction of memoryconsolidation associated with a neurodegenerative disease comprisesParkinson's disease.
 5. The method according to claim 2, wherein themammal is a human.
 6. The method according to claim 1, wherein themammal is a human.
 7. The method according to claim 3, wherein themammal is a human.